The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring, and potential delays in detecting virologic failure on transmitted and acquired genotypic antiretroviral resistance. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment. We have observed declining incidence among Rakai cohort participants since the introduction of ARVs and safe male circumcision with an even greater decline among men (benefiting from both MMC and exposure to female partners on treatment) supporting the current scale up of combination HIV prevention. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We measured the levels of transmitted antiretroviral drug resistance among 51 recently infected RCCS seroconverters with documented seroconversion between November 2012 and October 2013. We found low rates of transmitted antiretroviral drug resistance with only 2 individuals (4%) having resistance to NNRTIs and no resistance found to NRTIs or PIs. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings; most programs use clinical or immunological monitoring (IM) only. Our earlier studies revealed that routine viral load monitoring during the first 3 years of ART reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. Early viral load monitoring may also offer an additional tool to improve adherence and reduce the risk of virologic failure. Of 1,841 patients with at least 48 weeks of follow-up, 1,699 (92%) had an undetectable VL at 24 weeks (early suppressors). Of the remaining 142 (8%) patients who had a detectable VL at 24 weeks, 60% of whom went on to be undetectable at 48 weeks (late suppressors). The majority of late suppressors (84%) remained suppressed well beyond 48 weeks. Variables significantly predicting non-suppression by 48 weeks included: 24 week VL>2,000 copies/ml (OR=7.9; 95% CI 3.6-17.4) and age <30 (OR=2.8; 95% CI 1.3-6.2). The majority of patients with detectable VL at 24 weeks went on to full suppression that remained durable well beyond 48 weeks. In collaboration with other adult cohorts in Africa, we showed that delayed switch of antiretroviral therapy after virologic failure is associated with elevated mortality highlighting the importance of timely switching to second line regimens. It is unclear whether ongoing CD4 monitoring is needed following immunologic and virologic response to antiretroviral therapy (ART). We investigated the proportion of clients who achieved a virologic and immunologic response and then had a subsequent CD4 count<200 cells/ul despite continued virologic suppression. Included in this analysis were clients receiving ART through the Rakai Health Sciences Program between June 2004-May 2013 who achieved a CD4<200 cells/ul and VL<400 copies/ml and who had 3 sets of CD4 and VL measurements (defined as a sequence) within a 390 day period. Among 1553 clients, only 43 (2.8%) clients developed CD4 declines, the majority, 32/43 (74%), among individuals whose initial CD4 was <300 cells/ul. Of the 43 clients with CD4 declines, 24 had an additional CD4 measurement and 20/24 (83%) achieved a CD4>200 cell/ul on their next measurement (median 285 cells/ul; IQR 220-365). Clients who achieved an immunologic and virologic response to ART were unlikely to experience a subsequent CD4 count decline to <200 cells/ul, and among those experiencing a decline, the majority were transient in nature. Thus, ongoing CD4 monitoring could be omitted. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda. Our study of Acyclovir suppressive therapy among HIV-1/HSV-2 co-infected patients showed an overall reduction in HIV-1 disease progression by 25% compared to placebo (p=0.04). In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). In a secondary analysis, we found that the rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. We found a similar increase among these same women when we measured vaginal CMV shedding. We found no difference in HPV prevalence after ART suggesting that at least early immune reconstitution is insufficient to promote HPV clearance. Women who participated in the study were monitored every six months for changes in soluble CD14 (sCD14), a marker for monocyte activation, and CRP, a marker for general immune activation. Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the Acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multi-variant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 15% of initial levels. These data suggests that monocyte activation may play a minor role in the ability of daily Acyclovir use to slow HIV disease progression. Optimizing the HIV care cascade is a critical component to achieving an AIDS free generation globally. We continue to examine factors associated with success and challenges in the treatment cascade in Rakai. To evaluate strategies to improve engagement in HIV case and prevention, we conducted a randomized trial of peer supporters between July 2011-July 2013, 442 ART-nave, HIV-infected adult participants were randomized to peer support or standard of care. Baseline characteristics were balanced between arms: 62% of participants had previously visited a HIV clinic, 40% were already taking cotrimoxazole prophylaxis, and 31% were not in care (no previous HIV clinic visit and not on cotrimoxazole) at baseline. After a median follow-up of 363 days, intervention participants were more likely to report being in care (92% vs. 84%; p=0.018), on cotrimoxazole (89% vs. 81%; p=0.022), and adherent to safe water vessel use (23% vs. 14%; p=0.022). No significant effects were observed on ART initiation, bed net use, or sexual behaviors. The intervention effect was observed primarily among participants not in care at baseline (n=139) with 83% vs. 53% (p=0.003) of these intervention participants in care at follow-up compared to controls, 78% vs. 58% on cotrimoxazole (p=0.02), and 20% vs. 4% adherent to safe water vessel use (p=0.017). Peer support increased enrollment into care, cotrimoxazole adherence, and safe water vessel use among ART-nave, HIV-infected adults. Peer support may be an effective intervention to facilitate pre-ART care and prevention. In a separate clinical trial in Eastern Uganda, we showed that community support agents providing monthly support visits to clients in pre-ART care more than doubled the retention in care compared with the standard of care arm, underscoring this important low cost intervention to improve the upstream stages of the HIV treatment cascade.